MSH2 (human mutS homolog 2)

Identity

Other names	COCA1
	FCC1
	hMSH2
	HNPCC1
HGNC	MSH2
Location	2p22-p21
Location_base_pair	Starts at 47483767 and ends at 47563864 bp from pter ( according to hg18-Mar_2006).
Local_order	Between the FLJ40172 and MSH6 genes.

DNA/RNA

	Diagram of the MSH2 gene. Exons are represented by boxes (in scale) transcribed and untranscribed sequences in blue and yellow, with exon numbers on top and number of base pairs at the bottom. Introns are represented by black bars (not in scale) and the number of base pairs indicated. The arrows show the ATG and the stop codons respectively.
Description	The MSH2 gene is composed of 16 exons spanning in a region of 80098 bp.
Transcription	The transcribed mRNA has 3145 bp.

Protein

	Diagram of the MSH2 protein in scale. Numbers inside the blue boxes indicate the exon from which is translated each part of the protein. The boxes inside represent the DNA binding domain (red), the hMSH3/hMSH6 interaction domain (yellow) and the MutL homologs interaction domain (green); C: Carboxyl-terminal; N: Amino-terminal.
Description	Aminoacids: 934. Molecular Weight: 104.7 kDa. MSH2 is a protein involved in the mismatch repair process after DNA replication. It contains a DNA binding domain and two interaction domains, one for MSH3 or MSH6 and the other for MutL homologs (MLH1 and PMS2), located in two different regions of the gene.
Localisation	Nuclear
Function	MSH2 can bind to MSH6 or to MSH3 to form the MutS alpha or the MutS beta complexes respectively. While MutS alpha complex binds to base-base and insertion-deletion mismatches, MutS beta only binds to insertion-deletion mismatches. Upon binding to the mismatch, the MutS complex associates with the MutL complex (composed of MLH1 and PMS2), and recruits the proteins needed for DNA excision and repair. (See also: Repair of DNA double-strand breaks
Homology	MSH2 is homologue to the bacterial MutS gene and MSH2 homologues are also present in eukaryotes.

Mutations

Germinal

There are over 300 MSH2 germline mutations described along the gene that cause hereditary non-polyposis colorectal cancer (HNPCC, see below). Mutations do not occur in any particular hotspot or region of the gene and include either nucleotide substitutions (missense, nonsense and splicing errors) and insertions/deletions (gross or small). In most of these mutations the resulting protein is truncated. Although rare there are described some founding mutations which account for a high proportion of the HNPCC tumours in some specific populations. Some germline genetic changes have also been described in exons and introns as non pathogenic.

Somatic

Some sporadic mismatch repair deficient cases (sporadic MSI) with somatic MSH2 mutations are described.

Implicated in

Entity	HNPCC (Hereditary Non Polyposis Colorectal Cancer)
Disease	Predisposition to develop cancer, preferentially colorectal, but also in endometrium, , urinary tract, stomach, small bowel, biliary tract and brain.
Oncogenesis	MSH2 mutations in HNPCC account for about 25% of the total cases approximately. These mutations are inherited in one allele and later the other allele is lost by LOH. This leads to mismatch repair deficiency in this patients, which is the cause of the accumulation of mutations along the genome, causing microsatellite instability (MSI) and promoting tumorigenesis. It has also been described that low levels of MSI characterize MLH1 and MSH2 HNPCC carriers before tumour diagnosis.
Entity	MSI (MicroSatellite Instability)
Note	Tumours in which the molecular feature that leads to cancer is the lost of the mismatch repair (MMR) system.
Disease	This phenotype is present in 15% of colorectal, gastric and endometrial cancer, and has a lower incidence in some other tissues.
Prognosis	MSI tumours have better prognosis than the MicroSatellite Stable (MSS).
Oncogenesis	Few sporadic cases and about 25% of the HNPCC are due to different mutations in MSH2. These mutations are germline in HNPCC.
Entity	Muir-Torre syndrome
Disease	Coincidence of at least one sebaceous adenoma, epithelioma or carcinoma and one internal malignancy.
Oncogenesis	Muir-Torre syndrome is mainly due to inherited MSH2 mutations.

External links

	Nomenclature
HGNC	MSH2   7325
Entrez_Gene	MSH2  4436  mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)
	Cards
Atlas	MSH2ID340ch2p22
GeneCards	MSH2
Ensembl	MSH2 [Search_View]   ENSG00000095002 [Gene_View]  MSH2 [Vega]
Genatlas	MSH2
GeneLynx	MSH2
eGenome	MSH2
euGene	4436
	Genomic and cartography
GoldenPath	MSH2  -     chr2:47483767-47563864 +  2p21   [Description]    (hg18-Mar_2006)
Ensembl	MSH2 - 2p21 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	MSH2
	Gene and transcription
Genbank	AK222860 [ ENTREZ ]
Genbank	AK223284 [ ENTREZ ]
Genbank	AK296831 [ ENTREZ ]
Genbank	AK297763 [ ENTREZ ]
Genbank	AK299667 [ ENTREZ ]
RefSeq	NM_000251 [ SRS ]    NM_000251 [ ENTREZ ]
RefSeq	AC_000045 [ SRS ]    AC_000045 [ ENTREZ ]
RefSeq	AC_000134 [ SRS ]    AC_000134 [ ENTREZ ]
RefSeq	NC_000002 [ SRS ]    NC_000002 [ ENTREZ ]
RefSeq	NG_007110 [ SRS ]    NG_007110 [ ENTREZ ]
RefSeq	NT_022184 [ SRS ]    NT_022184 [ ENTREZ ]
RefSeq	NW_001838769 [ SRS ]    NW_001838769 [ ENTREZ ]
RefSeq	NW_927719 [ SRS ]    NW_927719 [ ENTREZ ]
CCDS	MSH2 CCDS - NCBI
AceView	MSH2 AceView - NCBI
Unigene	Hs.597656 [ SRS ]    Hs.597656 [ NCBI ]     HS597656 [ spliceNest ]
Fast-db	4888 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P43246 [ SRS]    P43246 [ EXPASY ]     P43246 [ INTERPRO ]     P43246 [ UNIPROT ] P43246 [ VarSplice ]
Prosite	PS00486 DNA_MISMATCH_REPAIR_2 [ SRS ]    PS00486 DNA_MISMATCH_REPAIR_2 [ Expasy ]
Interpro	IPR011184 DNA_mismatch_repair_MSH2 [ SRS ]    IPR011184 DNA_mismatch_repair_MSH2 [ EBI ]
Interpro	IPR007695 DNA_mismatch_repair_MutS-lik_N [ SRS ]    IPR007695 DNA_mismatch_repair_MutS-lik_N [ EBI ]
Interpro	IPR000432 DNA_mismatch_repair_MutS_C [ SRS ]    IPR000432 DNA_mismatch_repair_MutS_C [ EBI ]
Interpro	IPR007861 DNA_mismatch_repair_MutS_clamp [ SRS ]    IPR007861 DNA_mismatch_repair_MutS_clamp [ EBI ]
Interpro	IPR007860 DNA_mismatch_repair_MutS_connt [ SRS ]    IPR007860 DNA_mismatch_repair_MutS_connt [ EBI ]
Interpro	IPR007696 DNA_mismatch_repair_MutS_core [ SRS ]    IPR007696 DNA_mismatch_repair_MutS_core [ EBI ]
CluSTr	P43246
Pfam	PF01624 MutS_I [ SRS ]    PF01624 MutS_I [ Sanger ]    pfam01624 [ NCBI-CDD ]
Pfam	PF05188 MutS_II [ SRS ]    PF05188 MutS_II [ Sanger ]    pfam05188 [ NCBI-CDD ]
Pfam	PF05192 MutS_III [ SRS ]    PF05192 MutS_III [ Sanger ]    pfam05192 [ NCBI-CDD ]
Pfam	PF05190 MutS_IV [ SRS ]    PF05190 MutS_IV [ Sanger ]    pfam05190 [ NCBI-CDD ]
Pfam	PF00488 MutS_V [ SRS ]    PF00488 MutS_V [ Sanger ]    pfam00488 [ NCBI-CDD ]
Smart	SM00534 MUTSac [EMBL]
Smart	SM00533 MUTSd [EMBL]
Prodom	PD001263 MutS_C[INRA-Toulouse]
Prodom	P43246 MSH2_HUMAN [ Domain structure ]   P43246 MSH2_HUMAN  [ sequences sharing at least 1 domain ]
Blocks	P43246
PDB	2O8B [ SRS ]    2O8B [ PdbSum ],   2O8B [ IMB ]   2O8B [ RSDB ]
PDB	2O8C [ SRS ]    2O8C [ PdbSum ],   2O8C [ IMB ]   2O8C [ RSDB ]
PDB	2O8D [ SRS ]    2O8D [ PdbSum ],   2O8D [ IMB ]   2O8D [ RSDB ]
PDB	2O8E [ SRS ]    2O8E [ PdbSum ],   2O8E [ IMB ]   2O8E [ RSDB ]
PDB	2O8F [ SRS ]    2O8F [ PdbSum ],   2O8F [ IMB ]   2O8F [ RSDB ]
HPRD	00389
	Protein Interaction databases
DIP	P43246
IntAct	P43246
	Polymorphism : SNP, mutations, diseases
OMIM	114030;114400;120435;137800;158320;162200;276300;609309    [ map ]
GENECLINICS	114030;114400;120435;137800;158320;162200;276300;609309
SNP	MSH2 [dbSNP-NCBI]
SNP	NM_000251 [SNP-NCI]
SNP	MSH2 [GeneSNPs - Utah]  MSH2] [HGBASE - SRS]
HAPMAP	MSH2 [HAPMAP]
COSMIC	MSH2 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	MSH2
Genetic Association	MSH2
CDC HuGE	MSH2
	General knowledge
Family Browser	MSH2 [UCSC Family Browser]
SOURCE	NM_000251
SMD	Hs.597656
SAGE	Hs.597656
GO	nucleotide binding [Amigo]  nucleotide binding
GO	magnesium ion binding [Amigo]  magnesium ion binding
GO	four-way junction DNA binding [Amigo]  four-way junction DNA binding
GO	DNA binding [Amigo]  DNA binding
GO	DNA binding [Amigo]  DNA binding
GO	single-stranded DNA binding [Amigo]  single-stranded DNA binding
GO	ATP binding [Amigo]  ATP binding
GO	ATP binding [Amigo]  ATP binding
GO	nucleus [Amigo]  nucleus
GO	base-excision repair [Amigo]  base-excision repair
GO	mismatch repair [Amigo]  mismatch repair
GO	mismatch repair [Amigo]  mismatch repair
GO	postreplication repair [Amigo]  postreplication repair
GO	protein C-terminus binding [Amigo]  protein C-terminus binding
GO	ATPase activity [Amigo]  ATPase activity
GO	mismatched DNA binding [Amigo]  mismatched DNA binding
GO	guanine/thymine mispair binding [Amigo]  guanine/thymine mispair binding
GO	single guanine insertion binding [Amigo]  single guanine insertion binding
GO	single thymine insertion binding [Amigo]  single thymine insertion binding
GO	dinucleotide repeat insertion binding [Amigo]  dinucleotide repeat insertion binding
GO	MutSalpha complex [Amigo]  MutSalpha complex
GO	MutSalpha complex [Amigo]  MutSalpha complex
GO	MutSbeta complex [Amigo]  MutSbeta complex
GO	MutSbeta complex [Amigo]  MutSbeta complex
GO	oxidized purine DNA binding [Amigo]  oxidized purine DNA binding
GO	MutLalpha complex binding [Amigo]  MutLalpha complex binding
GO	protein homodimerization activity [Amigo]  protein homodimerization activity
GO	ADP binding [Amigo]  ADP binding
GO	maintenance of DNA repeat elements [Amigo]  maintenance of DNA repeat elements
GO	negative regulation of cell cycle [Amigo]  negative regulation of cell cycle
KEGG	Colorectal cancer
PubGene	MSH2
TreeFam	MSH2
CTD	4436 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	MSH2 Related clones (RZPD - Berlin)
	PubMed
PubMed	318 Pubmed reference(s) in Entrez

Bibliography

The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.

Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R

Cell. 1993 ; 75 (5) : 1027-1038.

PMID 8252616

Microsatellite instability in inherited and sporadic neoplasms.

Eshleman JR, Markowitz SD

Current opinion in oncology. 1995 ; 7 (1) : 83-89.

PMID 7696368

DNA mismatch repair defects: role in colorectal carcinogenesis.

Jacob S, Praz F

Biochimie. 2002 ; 84 (1) : 27-47.

PMID 11900875

DNA mismatch repair and mutation avoidance pathways.

Marti TM, Kunz C, Fleck O

Journal of cellular physiology. 2002 ; 191 (1) : 28-41.

PMID 11920679

Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review.

Mitchell RJ, Farrington SM, Dunlop MG, Campbell H

American journal of epidemiology. 2002 ; 156 (10) : 885-902.

PMID 12419761

A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States.

Lynch HT, Coronel SM, Okimoto R, Hampel H, Sweet K, Lynch JF, Barrows A, Wijnen J, van der Klift H, Franken P, Wagner A, Fodde R, de la Chapelle A

JAMA : the journal of the American Medical Association. 2004 ; 291 (6) : 718-724.

PMID 14871915

A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome.

Mangold E, Pagenstecher C, Leister M, Mathiak M, Rˆºtten A, Friedl W, Propping P, Ruzicka T, Kruse R

Journal of medical genetics. 2004 ; 41 (7) : 567-572.

PMID 15235030

Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis.

Alazzouzi H, Domingo E, Gonzˆ°lez S, Blanco I, Armengol M, Espˆ‚n E, Plaja A, Schwartz S, Capella G, Schwartz S Jr

Human molecular genetics. 2005 ; 14 (2) : 235-239.

PMID 15563510

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

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Contributor(s)

Written	07-2005	Enric Domingo, Sim Schwartz Jr
		Oncologia Molecular i Envelliment, Centre d'Investigacions en Bioquímica i Biologia Molecular (CIBBIM) Hospital Universitari Vall d'Hebron Passeig Vall d'Hebron 119-129 Barcelona 08035, Catalonia, Spain

Citation

This paper should be referenced as such :

Domingo E, Schwartz S Jr . MSH2 (human mutS homolog 2). Atlas Genet Cytogenet Oncol Haematol. July 2005 . URL : http://AtlasGeneticsOncology.org/Genes/MSH2ID340ch2p22.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Sun Nov 9 19:43:51 2008